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Aims: \ud Identifying novel mediators of lethal myocardial reperfusion injury that can be targeted during primary percutaneous coronary intervention (PPCI) is key to limiting the progression of patients with ST-elevated myocardial infarction (STEMI) to heart failure. Here we show through parallel clinical and integrative preclinical studies the significance of the protease cathepsin-L on cardiac function during reperfusion injury.\ud \ud Methods and Results: \ud We found that direct cardiac release of cathepsin-L in STEMI patients (n = 76) immediately post-PPCI leads to elevated serum cathepsin-L levels and that serum levels of cathepsin-L in the first 24 hour post-reperfusion are associated with reduced cardiac contractile function and increased infarct size. Preclinical studies, demonstrate that inhibition of cathepsin-L release following reperfusion injury with CAA0225 reduces infarct size and improves cardiac contractile function by limiting abnormal cardiomyocyte calcium handling and apoptosis.\ud \ud Conclusion: \ud Our findings suggest that cathepsin-L is a novel therapeutic target that could be exploited clinically to counteract the deleterious effects of acute reperfusion injury after an acute STEMI.\ud \ud Translational perspective: \ud New therapeutic targets are urgently required to limit myocardial damage after reperfusion injury. We identified cardiac release of the protease cathepsin-L among patients following primary percutaneous coronary intervention (PPCI). Elevated serum levels of cathepsin-L were associated with reduced contractile function and increased infarct size at 24 hour and 6 months post-PPCI. Work conducted using animal models indicated that cardiac release of cathepsin-L mediated cardiac dysfunction following reperfusion injury. Specific inhibition of cathepsin-L prevented abnormal calcium handling, reduced infarct size and improved contractile function. These novel findings offer the prospect of targeting cathepsin-L-mediated cardiac dysfunction after PPCI.

BACKGROUND Novel parameters that detect failed microvascular reperfusion might identify better the patients likely to benefit from adjunctive treatments during primary percutaneous coronary intervention (PCI). AIMS The aim of this study was to test the hypothesis that a novel invasive parameter, the thermodilution-derived temperature recovery time (TRT), would be associated with microvascular obstruction (MVO) and prognosis. METHODS TRT was derived and validated in two independent ST-elevation myocardial infarction populations and was measured immediately post PCI. TRT was defined as the duration (seconds) from the nadir of the hyperaemic thermodilution curve to 20% from baseline body temperature. MVO extent (% left ventricular mass) was assessed by cardiovascular magnetic resonance imaging at 2-7 days. RESULTS In the retrospective derivation cohort (n=271, mean age 60±12 years, 72% male), higher TRT was associated with more MVO (coefficient: 4.09 [95% CI: 2.70-5.48], p 32, CFR ≤2, hyperaemic Tmn >median, thermodilution waveform, age and ischaemic time. At five years, higher TRT was multivariably associated with all-cause death/heart failure hospitalisation (OR 4.14 [95% CI: 2.08-8.25], p

BACKGROUND Intravascular lithotripsy (IVL) is a novel alternative to rotational atherectomy (RA) for the modification of heavily calcified coronary stenoses prior to percutaneous coronary intervention (PCI). We compare the real-world resource utilisation and associated costs of PCI with adjunctive RA and IVL. METHODS We compared the resource utilisation, in-lab consumable costs and procedural data of 120 patients who underwent PCI with IVL from the Disrupt-CAD II study (NCT03328949) to 60 patients who underwent PCI with RA at the Golden Jubilee National Hospital, Glasgow. The RA patients were consecutive and selected on the basis of being deemed suitable for IVL by an independent interventional cardiologist experienced in the use of both techniques. RESULTS PCI with IVL was associated with significantly lower costs than PCI with RA (mean difference £398 [95% CI, £181-£615]; p

ObjectivesPersistently impaired culprit artery flow (MethodsIn T-TIME (trial of low-dose adjunctive alTeplase during primary PCI), patients ≤6 hours from onset of ST-elevation myocardial infarction (STEMI) were randomised to placebo, alteplase 10 mg or alteplase 20 mg, administered by infusion into the culprit artery, pre-stenting. In this prespecified, secondary analysis, coronary flow was assessed angiographically at the point immediately before drug administration. Microvascular obstruction, myocardial haemorrhage and infarct size were assessed by cardiovascular magnetic resonance (CMR) at 2–7 days and 3 months.ResultsTIMI flow was assessed after first treatment (balloon angioplasty/aspiration thrombectomy), immediately pre-drug administration, in 421 participants (mean age 61±10 years, 85% male) and was 3, 2 or 1 in 267, 134 and 19 participants respectively. In patients with TIMI flow ≤2 pre-drug, there was higher incidence of microvascular obstruction with alteplase (alteplase 20 mg (53.1%) and 10 mg (59.5%) combined versus placebo (34.1%); OR=2.47 (95% CI 1.16 to 5.22, p=0.018) interaction p=0.005) and higher incidence of myocardial haemorrhage (alteplase 20 mg (53.1%) and 10 mg (57.9%) combined vs placebo (27.5%); OR=3.26 (95% CI 1.44 to 7.36, p=0.004) interaction p=0.001). These effects were not observed in participants with TIMI 3 flow pre-drug. There were no interactions between TIMI flow pre-drug, alteplase and 3-month CMR findings.ConclusionIn patients with impaired culprit artery flow (Trial registration numberNCT02257294.

Background Segmental extent of infarction assessed by late gadolinium enhancement (LGE) imaging early post‐ST‐segment elevation myocardial infarction (STEMI) has utility in predicting left ventricular functional recovery. Hypothesis: We hypothesized that segmental circumferential strain with displacement encoding with stimulated echoes (DENSE) would be a stronger predictor of infarct transmurality than feature‐tracking strain, and noninferior to extracellular volume fraction (ECV). Study Type: Prospective. Population: Fifty participants (mean ± SD, 59 ± 9 years, 40 [80%] male) underwent cardiac MRI on day 1 post‐STEMI. Field‐Strength/Sequences: 1.5T/cine, DENSE , T1 mapping, ECV , LGE. Assessment Two observers assessed segmental percentage LGE extent, presence of microvascular obstruction (MVO), circumferential and radial strain with DENSE and feature‐tracking, T1 relaxation times, and ECV. Statistical Tests: Normality was tested using the Shapiro–Wilk test. Skewed distributions were analyzed utilizing Mann–Whitney or Kruskal–Wallis tests and normal distributed data using independent t ‐tests. Diagnostic cutoff values were identified using the Youden index. The difference in area under the curve was compared using the z‐statistic. Results: Segmental circumferential strain with DENSE was associated with the extent of infarction ≥50% (AUC [95% CI], cutoff value = 0.9 [0.8, 0.9], −10%) similar to ECV (AUC = 0.8 [0.8, 0.9], 37%) (P = 0.117) and superior to feature‐tracking circumferential strain (AUC = 0.7[0.7, 0.8], −19%) (P

IntroductionThere is conflicting evidence regarding the benefits of percutaneous coronary intervention (PCI) in patients with grey zone fractional flow reserve (GZFFR artery) values (0.75–0.80). The prevalence of ischaemia is unknown. We wished to define the prevalence of ischaemia inGZFFR artery and assess whether PCI is superior to optimal medical therapy (OMT) for angina control.MethodsWe enrolled 104 patients with angina with 1:1 randomisation to PCI or OMT. The artery was interrogated with a Doppler flow/pressure wire. Patients underwent Magnetic Resonance Imaging (MRI) with follow-up at 3 and 12 months. The primary outcome was angina status at 3 months using the Seattle Angina Questionnaire (SAQ).Results104 patients (age 60±9 years), 79 (76%) males and 79 (76%) Left Anterior Descending (LAD) stenoses were randomised. Coronary physiology and SAQ were similar. Of 98 patients with stress perfusion MRI data, 17 (17%) had abnormal perfusion (≥2 segments with ≥25% ischaemia or ≥1 segment with ≥50% ischaemia) in the targetGZFFR artery. Of 89 patients with invasive physiology data, 26 (28%) had coronary flow velocity reserve GZFFR artery. After 3 months of follow-up, compared with patients treated with OMT only, patients treated by PCI and OMT had greater improvements in SAQ angina frequency (21 (28) vs 10 (23); p=0.026) and quality of life (24 (26) vs 11 (24); p=0.008) though these differences were no longer significant at 12 months.ConclusionsNon-invasive evidence of major ischaemia is uncommon in patients withGZFFR artery. Compared with OMT alone, patients randomised to undergo PCI reported improved symptoms after 3 months but these differences were no longer significant after 12 months.Trial registration numberNCT02425969.

Objectives The aim of this study was to test the hypothesis that invasive coronary function testing at time of angiography could help stratify management of angina patients without obstructive coronary artery disease. Background Medical therapy for angina guided by invasive coronary vascular function testing holds promise, but the longer-term effects on quality of life and clinical events are unknown among patients without obstructive disease. Methods A total of 151 patients with angina with symptoms and/or signs of ischemia and no obstructive coronary artery disease were randomized to stratified medical therapy guided by an interventional diagnostic procedure versus standard care (control group with blinded interventional diagnostic procedure results). The interventional diagnostic procedure–facilitated diagnosis (microvascular angina, vasospastic angina, both, or neither) was linked to guideline-based management. Pre-specified endpoints included 1-year patient-reported outcome measures (Seattle Angina Questionnaire, quality of life [EQ-5D]) and major adverse cardiac events (all-cause mortality, myocardial infarction, unstable angina hospitalization or revascularization, heart failure hospitalization, and cerebrovascular event) at subsequent follow-up. Results Between November 2016 and December 2017, 151 patients with ischemia and no obstructive coronary artery disease were randomized (n = 75 to the intervention group, n = 76 to the control group). At 1 year, overall angina (Seattle Angina Questionnaire summary score) improved in the intervention group by 27% (difference 13.6 units; 95% confidence interval: 7.3 to 19.9; p, Central Illustration

Aims A fractional flow reserve (FFR) value ≥0.90 after percutaneous coronary intervention (PCI) is associated with a reduced risk of adverse cardiovascular events. TARGET-FFR is an investigator-initiated, single-centre, randomized controlled trial to determine the feasibility and efficacy of a post-PCI FFR-guided optimization strategy vs. standard coronary angiography in achieving final post-PCI FFR values ≥0.90. Methods and results After angiographically guided PCI, patients were randomized 1:1 to receive a physiology-guided incremental optimization strategy (PIOS) or a blinded coronary physiology assessment (control group). The primary outcome was the proportion of patients with a final post-PCI FFR ≥0.90. Final FFR ≤0.80 was a prioritized secondary outcome. A total of 260 patients were randomized (131 to PIOS, 129 to control) and 68.1% of patients had an initial post-PCI FFR Conclusion Over two-thirds of patients had a physiologically suboptimal result after angiography-guided PCI. An FFR-guided optimization strategy did not significantly increase the proportion of patients with a final FFR ≥0.90, but did reduce the proportion of patients with a final FFR ≤0.80.

Aim Coronary angiography is indicated in many patients with known or suspected angina for the investigation of coronary artery disease (CAD). However, up to half of patients with symptoms of ischaemia have no obstructive coronary arteries (INOCA). This large subgroup includes patients with suspected microvascular angina (MVA) and/or vasospastic angina (VSA). Clinical guidelines relating to the management of patients with INOCA are limited. Uncertainty regarding the diagnosis of patients with INOCA presents a health economic challenge, both in terms of healthcare resource utilisation and of quality-of-life impact on patients. Methods A cost-effectiveness analysis of the introduction of stratified medicine into the invasive management of INOCA, based on clinical and resource-use data obtained in the CorMicA trial, from a UK NHS perspective. The intervention included an invasive diagnostic procedure (IDP) of coronary vascular function during coronary angiography to define clinical endotypes to target with linked medical therapy. Outcomes of interest were mean total cost and QALY gain between treatment groups, and the incremental cost-effectiveness ratio. We undertook probabilistic sensitivity and scenario analyses. Results The incremental cost per QALY gained at 12 months was £4500 (£2937, £33264). Compared with a willingness-to-pay (WTP) threshold of £20,000 per QALY, the use of the IDP test is cost-effective. At this WTP threshold there is a 96% probability of the IDP being cost-effective, based on the uncertainty described by bootstrap analysis. Conclusions The burden of INOCA, particularly in women, is known to be significant. These findings provided new evidence to inform this unmet clinical need.

Background: Patients with angina symptoms and/or signs of ischemia but no obstructive coronary artery disease (INOCA) pose a diagnostic and therapeutic challenge.Objectives: The purpose of ...

Background: The index of microcirculatory resistance (IMR) of the infarct-related artery and left ventricular end-diastolic pressure (LVEDP) are acute, prognostic biomarkers in patients undergoing primary percutaneous coronary intervention. The clinical significance of IMR and LVEDP in combination is unknown. Methods: IMR and LVEDP were prospectively measured in a prespecified substudy of the T-TIME clinical trial (Trial of Low Dose Adjunctive Alteplase During Primary PCI). IMR was measured using a pressure- and temperature-sensing guidewire following percutaneous coronary intervention. Prognostically established thresholds for IMR (>32) and LVEDP (>18 mm Hg) were predefined. Contrast-enhanced cardiovascular magnetic resonance imaging (1.5 Tesla) was acquired 2 to 7 days and 3 months postmyocardial infarction. The primary end point was major adverse cardiac events, defined as cardiac death/nonfatal myocardial infarction/heart failure hospitalization at 1 year. Results: IMR and LVEDP were both measured in 131 patients (mean age 59±10.7 years, 103 [78.6%] male, 48 [36.6%] with anterior myocardial infarction). The median IMR was 29 (interquartile range, 17–55), the median LVEDP was 17 mm Hg (interquartile range, 12–21), and the correlation between them was not statistically significant ( r =0.15; P =0.087). Fifty-three patients (40%) had low IMR (≤32) and low LVEDP (≤18), 18 (14%) had low IMR and high LVEDP, 31 (24%) had high IMR and low LVEDP, while 29 (22%) had high IMR and high LVEDP. Infarct size (% LV mass), LV ejection fraction, final myocardial perfusion grade ≤1, TIMI (Thrombolysis In Myocardial Infarction) flow grade ≤2, and coronary flow reserve were associated with LVEDP/IMR group, as was hospitalization for heart failure (n=18 events; P =0.045) and major adverse cardiac events (n=21 events; P =0.051). LVEDP>18 and IMR>32 combined was associated with major adverse cardiac events, independent of age, estimated glomerular filtration rate, and infarct-related artery (odds ratio, 5.80 [95% CI, 1.60–21.22] P =0.008). The net reclassification improvement for detecting major adverse cardiac events was 50.6% (95% CI, 2.7–98.2; P =0.033) when LVEDP>18 was added to IMR>32. Conclusions: IMR and LVEDP in combination have incremental value for risk stratification following primary percutaneous coronary intervention. Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02257294.

Background Microvascular obstruction commonly affects patients with acute ST-segment elevation myocardial infarction and is independently associated with adverse outcomes. Objective To determine whether or not a strategy involving low-dose intracoronary fibrinolytic therapy infused early after coronary reperfusion will reduce microvascular obstruction. Design This was a multicentre, randomised, double-blind, parallel-group, placebo-controlled, dose-ranging trial. Setting The trial took place at 11 hospitals in the UK between 17 March 2016 and 21 December 2017. Participants Patients with acute ST-segment elevation myocardial infarction and a symptom onset to reperfusion time of ≤ 6 hours were eligible for randomisation. Radial artery access was a requirement, and further angiographic criteria included a proximal-to-middle coronary artery occlusion or impaired coronary flow in the presence of a definite thrombus in the culprit coronary artery. Exclusion criteria included a functional coronary collateral supply to the infarct-related artery, any contraindication to fibrinolysis and lack of informed consent. Additional exclusion criteria for safety were (1) requirement for immunosuppressive drug therapy for ≤ 3 months and (2) treatment with an antimicrobial agent. Intervention A total of 440 participants were randomly assigned 1 : 1 : 1 to treatment with placebo (n = 151), 10 mg of alteplase (n = 144) or 20 mg of alteplase (n = 145) administered by manual infusion directly into the infarct-related coronary artery over 5–10 minutes. The intervention was scheduled to happen after reperfusion and before stent implantation. Outcomes The primary outcome was the amount of microvascular obstruction (percentage of left ventricular mass) demonstrated by contrast-enhanced cardiac magnetic resonance imaging at 2–7 days after enrolment. The primary analysis was the comparison between the 20 mg of alteplase group and the placebo group; if this comparison was not significant, the comparison of the 10 mg of alteplase group with the placebo group was considered as a secondary analysis. Sample size A total of 618 patients (minimum of 558 patients). Recruitment was halted on 21 December 2017 given that conditional power for the primary outcome based on a prespecified analysis of the first 267 randomised participants was Methods The primary outcome was compared between groups using a stratified Wilcoxon rank-sum test (van Elteren test), stratified by the location of the myocardial infarction. Results Among the 440 patients (mean age of 60.5 years; 15% women), the primary end point was measured in 396 (90%) patients, 17 (3.9%) withdrew, seven died and all other patients were followed up to 3 months. The amount (mean percentage of left ventricular mass) of microvascular obstruction was 2.3% versus 2.6% versus 3.5% in the placebo, 10 mg of alteplase and 20 mg of alteplase groups, respectively. In the primary analysis, microvascular obstruction did not differ between the 20 mg of alteplase group and the placebo group: 3.5% versus 2.3%, estimated difference 1.16% (95% confidence interval –0.08% to 2.41%; p = 0.32). In the secondary analysis, microvascular obstruction did not differ between the 10 mg of alteplase group and the placebo group: 2.6% versus 2.3%, estimated difference 0.29% (95% confidence interval –0.76% to 1.35%; p = 0.74). By 3 months, major adverse cardiac events (cardiac death, non-fatal myocardial infarction and unplanned hospitalisation for heart failure) had occurred in 15 (10.1%) patients in the placebo group, 18 (12.9%) in the 10 mg of alteplase group and 12 (8.2%) in the 20 mg of alteplase group. Conclusions Adjunctive low-dose intracoronary alteplase given during the primary percutaneous intervention did not reduce microvascular obstruction compared with placebo. Limitations Premature discontinuation of enrolment limited the power of the secondary and safety analyses. Future work Low-dose intracoronary alteplase or tenecteplase could be compared with placebo at the end of primary percutaneous coronary intervention in patients with an ischaemic time of Trial registration This trial is registered as ClinicalTrials.gov NCT02257294. Funding This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a Medical Research Council (MRC) and National Institute for Health Research (NIHR) partnership. This will be published in full in Efficacy and Mechanism Evaluation; Vol. 7, No. 5. See the NIHR Journals Library website for further project information.

Background Angina is associated with impaired quality of life and an adverse prognosis. Purpose Prospectively evaluate quality of life and clinical outcomes in patients with angina undergoing invasive coronary angiography according to endotype: symptoms and/or signs of ischaemia and no obstructive coronary artery disease (INOCA) compared to obstructive coronary artery disease subjects managed by medical therapy, revascularization with percutaneous coronary intervention (PCI) and coronary artery bypass graft (CABG) surgery, respectively. Methods We conducted a prospective clinical evaluation of patients with angina undergoing clinically indicated invasive management (NCT03193294). Symptom severity and quality of life were assessed at baseline and repeated after 6 months. Comparisons between treatment groups were based on analysis of covariance general linear models adjusting for baseline score, sex, and cardiovascular risk. INOCA subjects were considered as one diagnostic group and not all subjects had invasive vasoreactivity testing. Results 391 patients (mean age 62±10 years, 52% female) were enrolled over 12 months and classified into one of four groups: INOCA (N=185; 47%), obstructive CAD treated by PCI (N=126; 32%), obstructive CAD treated by CABG (N=48; 12%) and obstructive CAD managed with medical therapy (N=32; 8%). After adjusting for between group differences and overall risk, INOCA subjects had worse angina and worse treatment response at follow up (21% and 27% reduction in angina score compared to CAD patients revascularized with PCI and CABG respectively). INOCA subjects had numerically lower treatment response than CAD patients managed with medications (6.4 units, −12%; P=0.181). Population baseline mean Seattle Angina Questionnaire (SAQ) frequency score (60±26) and SAQ summary score (52.5±19) were similar between groups. The absolute difference was 6.4 units versus medically managed CAD (95% CI: −3.0 to 15.9; P=0.181), 11.3 units versus the CAD group undergoing PCI (6.1 to 16.5; P Conclusion(s) Patients with INOCA had more severe angina symptoms reflecting worse quality of life and treatment response at 6 months with similar MACE as CAD subjects even after adjustment for confounding factors. This study highlights the need for evidence-based antianginal therapies and disease-modifying treatments for angina patients regardless of the presence of obstructive coronary disease. Figure 1 Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): This work was funded by the British Heart Foundation (PG/17/2532884; RE/13/5/30177; RE/18/6134217)

Background: Cut off values for change in left ventricular end-diastolic volume (LVEDV) and LV end-systolic volume (LVESV) by cardiovascular magnetic resonance following ST-segment–elevation myocardial infarction have recently been proposed and 4 patterns of LV remodeling were described. We aimed to assess their long-term prognostic significance. Methods: A prospective cohort of unselected patients with ST-segment–elevation myocardial infarction with paired acute and 6-month cardiovascular magnetic resonance, with the 5-year composite end point of all-cause death and hospitalization for heart failure was included. The prognosis of the following groups (group 1: reverse LV remodeling [≥12% decrease in LVESV]; group 2: no LV remodeling [changes in LVEDV and LVESV Results: Two hundred eighty-five patients were included with a median follow-up was 5.8 years. The composite end point occurred in 9.5% in group 1, 12.3% in group 2, 7.1% in group 3, and 24.2% in group 4. Group 4 had significantly higher cumulative event rates of the composite end point (log-rank test, P =0.03) with the other 3 groups showing similar cumulative event rates (log-rank test, P =0.51). Cox proportional hazard for group 2 (hazard ratio, 1.3 [95% CI, 0.6–3.1], P =0.53) and group 3 (hazard ratio, 0.6 [95% CI, 0.2–2.3], P =0.49) were not significantly different but was significantly higher in group 4 (hazard ratio, 3.0 [95% CI, 1.2–7.1], P =0.015) when compared with group 1. Conclusions: Patients with ST-segment–elevation myocardial infarction developing adverse LV remodeling at 6 months, defined as ≥12% increase in both LVESV and LVEDV by cardiovascular magnetic resonance, was associated with worse long-term clinical outcomes than those with adverse LV remodeling with compensation, reverse LV remodeling, and no LV remodeling, with the latter 3 groups having similar outcomes in a cohort of stable reperfused patients with ST-segment–elevation myocardial infarction. Registration URL: http://www.clinicaltrials.gov . Unique identifier: NCT02072850.

Supplemental Digital Content is available in the text., Background: The resistive reserve ratio (RRR) expresses the ratio between basal and hyperemic microvascular resistance. RRR measures the vasodilatory capacity of the microcirculation. We compared RRR, index of microcirculatory resistance (IMR), and coronary flow reserve (CFR) for predicting microvascular obstruction (MVO), myocardial hemorrhage, infarct size, and clinical outcomes, after ST-segment–elevation myocardial infarction. Methods: In the T-TIME trial (Trial of Low-Dose Adjunctive Alteplase During Primary PCI), 440 patients with acute ST-segment–elevation myocardial infarction from 11 UK hospitals were prospectively enrolled. In a subset of 144 patients, IMR, CFR, and RRR were measured post-primary percutaneous coronary intervention. MVO extent (% left ventricular mass) was determined by cardiovascular magnetic resonance imaging at 2 to 7 days. Infarct size was determined at 3 months. One-year major adverse cardiac events, heart failure hospitalizations, and all-cause death/heart failure hospitalizations were assessed. Results: In these 144 patients (mean age, 59±11 years, 80% male), median IMR was 29.5 (interquartile range: 17.0–55.0), CFR was 1.4 (1.1–2.0), and RRR was 1.7 (1.3–2.3). MVO occurred in 41% of patients. IMR>40 was multivariably associated with more MVO (coefficient, 0.53 [95% CI, 0.05–1.02]; P=0.031), myocardial hemorrhage presence (odds ratio [OR], 3.20 [95% CI, 1.25–8.24]; P=0.016), and infarct size (coefficient, 5.05 [95% CI, 0.84–9.26]; P=0.019), independently of CFR≤2.0, RRR≤1.7, myocardial perfusion grade≤1, and Thrombolysis in Myocardial Infarction frame count. RRR was multivariably associated with MVO extent (coefficient, −0.60 [95% CI, −0.97 to −0.23]; P=0.002), myocardial hemorrhage presence (OR, 0.34 [95% CI, 0.15–0.75]; P=0.008), and infarct size (coefficient, −3.41 [95% CI, −6.76 to −0.06]; P=0.046). IMR>40 was associated with heart failure hospitalization (OR, 5.34 [95% CI, 1.80–15.81] P=0.002), major adverse cardiac events (OR, 4.46 [95% CI, 1.70–11.70] P=0.002), and all-cause death/heart failure hospitalization (OR, 4.08 [95% CI, 1.55–10.79] P=0.005). RRR was associated with heart failure hospitalization (OR, 0.44 [95% CI, 0.19–0.99] P=0.047). CFR was not associated with infarct characteristics or clinical outcomes. Conclusions: In acute ST-segment–elevationl infarction, IMR and RRR, but not CFR, were associated with MVO, myocardial hemorrhage, infarct size, and clinical outcomes. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02257294.

Aims Endothelin-1 (ET-1) is a potent vasoconstrictor peptide linked to vascular diseases through a common intronic gene enhancer [(rs9349379-G allele), chromosome 6 (PHACTR1/EDN1)]. We performed a multimodality investigation into the role of ET-1 and this gene variant in the pathogenesis of coronary microvascular dysfunction (CMD) in patients with symptoms and/or signs of ischaemia but no obstructive coronary artery disease (CAD). Methods and results Three hundred and ninety-one patients with angina were enrolled. Of these, 206 (53%) with obstructive CAD were excluded leaving 185 (47%) eligible. One hundred and nine (72%) of 151 subjects who underwent invasive testing had objective evidence of CMD (COVADIS criteria). rs9349379-G allele frequency was greater than in contemporary reference genome bank control subjects [allele frequency 46% (129/280 alleles) vs. 39% (5551/14380); P = 0.013]. The G allele was associated with higher plasma serum ET-1 [least squares mean 1.59 pg/mL vs. 1.28 pg/mL; 95% confidence interval (CI) 0.10–0.53; P = 0.005]. Patients with rs9349379-G allele had over double the odds of CMD [odds ratio (OR) 2.33, 95% CI 1.10–4.96; P = 0.027]. Multimodality non-invasive testing confirmed the G allele was associated with linked impairments in myocardial perfusion on stress cardiac magnetic resonance imaging at 1.5 T (N = 107; GG 56%, AG 43%, AA 31%, P = 0.042) and exercise testing (N = 87; −3.0 units in Duke Exercise Treadmill Score; −5.8 to −0.1; P = 0.045). Endothelin-1 related vascular mechanisms were assessed ex vivo using wire myography with endothelin A receptor (ETA) antagonists including zibotentan. Subjects with rs9349379-G allele had preserved peripheral small vessel reactivity to ET-1 with high affinity of ETA antagonists. Zibotentan reversed ET-1-induced vasoconstriction independently of G allele status. Conclusion We identify a novel genetic risk locus for CMD. These findings implicate ET-1 dysregulation and support the possibility of precision medicine using genetics to target oral ETA antagonist therapy in patients with microvascular angina. Trial registration ClinicalTrials.gov: NCT03193294.

No abstract available.

Background Impaired microcirculatory reperfusion worsens prognosis following acute ST ‐segment–elevation myocardial infarction. In the T‐ TIME (A Trial of Low‐Dose Adjunctive Alteplase During Primary PCI) trial, microvascular obstruction on cardiovascular magnetic resonance imaging did not differ with adjunctive, low‐dose, intracoronary alteplase (10 or 20 mg) versus placebo during primary percutaneous coronary intervention. We evaluated the effects of intracoronary alteplase, during primary percutaneous coronary intervention, on the index of microcirculatory resistance, coronary flow reserve, and resistive reserve ratio. Methods and Results A prespecified physiology substudy of the T‐ TIME trial. From 2016 to 2017, patients with ST ‐segment–elevation myocardial infarction ≤6 hours from symptom onset were randomized in a double‐blind study to receive alteplase 20 mg, alteplase 10 mg, or placebo infused into the culprit artery postreperfusion, but prestenting. Index of microcirculatory resistance, coronary flow reserve, and resistive reserve ratio were measured after percutaneous coronary intervention. Cardiovascular magnetic resonance was performed at 2 to 7 days and 3 months. Analyses in relation to ischemic time (P =0.013), resistive reserve ratio ( P =0.026), and microvascular obstruction ( P =0.022), but not index of microcirculatory resistance. Conclusions In ST ‐segment–elevation myocardial infarction with ischemic time ≤6 hours, there was overall no difference in microvascular function with alteplase versus placebo. Clinical Trial Registration URL : https://www.clinicaltrials.gov . Unique identifier: NCT 02257294.

Supplemental Digital Content is available in the text., The rationale for our study was to investigate the pathophysiology of microvascular injury in patients with acute ST-segment–elevation myocardial infarction in relation to a history of hypertension. We undertook a cohort study using invasive and noninvasive measures of microvascular injury, cardiac magnetic resonance imaging at 2 days and 6 months, and assessed health outcomes in the longer term. Three hundred twenty-four patients with acute myocardial infarction (mean age, 59 [12] years; blood pressure, 135 [25] / 79 [14] mm Hg; 237 [73%] male, 105 [32%] with antecedent hypertension) were prospectively enrolled during emergency percutaneous coronary intervention. Compared with patients without antecedent hypertension, patients with hypertension were older (63 [12] years versus 57 [11] years; P

Supplemental Digital Content is available in the text., Background: Determine the prevalence and correlates of microvascular and vasospastic angina in patients with symptoms and signs of ischemia but no obstructive coronary artery disease (INOCA). Methods: Three hundred ninety-one patients with angina were enrolled at 2 regional centers over 12 months from November 2016 (NCT03193294). INOCA subjects (n=185; 47%) had more limiting dyspnea (New York Heart Association classification III/IV 54% versus 37%; odds ratio [OR], 2.0 [1.3–3.0]; P=0.001) and were more likely to be female (68% INOCA versus 38% in coronary artery disease; OR, 1.9 [1.5 to 2.5]; P

Background Microvascular obstruction affects one-half of patients with ST-segment elevation myocardial infarction and confers an adverse prognosis. Objectives This study aimed to determine whether the efficacy and safety of a therapeutic strategy involving low-dose intracoronary alteplase infused early after coronary reperfusion associates with ischemic time. Methods This study was conducted in a prospective, multicenter, parallel group, 1:1:1 randomized, dose-ranging trial in patients undergoing primary percutaneous coronary intervention. Ischemic time, defined as the time from symptom onset to coronary reperfusion, was a pre-specified subgroup of interest. Between March 17, 2016, and December 21, 2017, 440 patients, presenting with ST-segment elevation myocardial infarction within 6 h of symptom onset (, Central Illustration

Background Microvascular obstruction affects half of patients with acute ST-segment elevation myocardial infarction and confers an adverse prognosis. Purpose We aimed to determine whether the efficacy and safety of a therapeutic strategy involving low-dose intra-coronary alteplase infused early after coronary reperfusion associates with ischaemic time. Methods We conducted a prospective, multicentre, parallel group, 1:1:1 randomised, dose-ranging trial in patients undergoing primary percutaneous coronary intervention. Ischaemic time, defined as the time from symptom onset to coronary reperfusion, was a pre-specified sub-group of interest. Between March 17, 2016, and December 21, 2017, 440 patients presenting at 11 hospitals in the UK were enrolled with follow up to 3 months. Patients with acute myocardial infarction due to occlusion of a major coronary artery presenting ≤6 hours from symptom onset were randomly assigned to treatment with placebo, alteplase 10mg or alteplase 20mg. The primary outcome was the amount of microvascular obstruction disclosed by cardiac magnetic resonance imaging at 2–7 days. Secondary outcomes included infarct size, myocardial haemorrhage, left ventricular ejection fraction, and troponin T area-under-the curve. Results 440 patients were randomized (figure), the primary endpoint was achieved in 396 (90%), seventeen (3.9%) withdrew and all other patients were followed up to 3 months. In the primary analysis, the amount of microvascular obstruction did not differ between the groups. Their ischaemic times were: ≤2 hours, n=98; ≥2– In patients with an ischaemic time ≥4 hours, treatment with alteplase (10 mg, n=26; 20 mg, n=30) was associated with a dose dependent increase in the amount (mean) of microvascular obstruction (% left ventricular mass) compared to placebo (n=27) 1.14 vs. 3.11 vs. 5.20; mean difference on square root scale 0.81 (95% CI 0.21, 1.42), p=0.009. The interaction test between ischaemic time and treatment (active vs. placebo) was not statistically significant p=0.06, however when the interaction was assessed for a trend across treatment groups this did reach statistical significance, p=0.018. Furthermore, a higher proportion of patients presenting ≥4–6 hours treated with 20 mg of alteplase had myocardial haemorrhage (59.3%) compared to the placebo group (28.0%), odds ratio 3.81 (95% CI 1.19, 12.25), p=0.025. The amount of haemorrhage was also greater; estimated mean difference 3.49 (95% CI 1.22, 5.75), p=0.0026. No between-treatment group differences for myocardial haemorrhage were observed in patients presenting with shorter ischaemic times. Study flow diagram Conclusions In patients presenting with an ischaemic time ≥4 hours, adjunctive treatment with low-dose intra-coronary alteplase during primary PCI was associated with increases in microvascular obstruction and myocardial haemorrhage. The mechanism may involve haemorrhagic transformation within the infarct core. Acknowledgement/Funding NIHR EME programme (reference: 12/170/45); British Heart Foundation (BHF reference FS/16/74/32573)

Background Impaired microcirculatory reperfusion worsens prognosis post-primary percutaneous coronary intervention (PCI) for ST-elevation myocardial infarction (STEMI). Intracoronary (IC) alteplase targets persisting thrombus post-reperfusion & distal embolisation. In the T-TIME trial microvascular obstruction on cardiac magnetic resonance (CMR) did not differ with IC alteplase vs placebo. Purpose To prospectively determine if index of microcirculatory resistance (IMR) is lower & coronary flow reserve (CFR) or resistive reserve ratio (RRR) are higher (improved) with IC alteplase, & to provide mechanistic insights. Methods A pre-planned substudy of the main protocol. From 2016–2017, STEMI patients from 3 UK hospitals ≤6 hrs ischaemic time were randomised in a 1:1:1 dose-ranging, double-blind design. Following standard care reperfusion, alteplase (10 or 20mg) or placebo was infused over 5–10 mins proximal to the culprit lesion pre-stenting. IMR (primary outcome), CFR & RRR (secondary outcomes) were measured in the culprit artery post-PCI. Physiology results were obscured from clinicians acquiring the data, to maintain blinding. CMR was performed 2 days & 3 months post-STEMI. Subgroup analyses were prespecified including by ischaemic time (4 hrs) & IMR threshold >32. Results In 144 patients (mean age 59 yrs, 80% male), IMR, CFR or RRR post-PCI did not differ with alteplase vs placebo (Table). Patients with ischaemic time 32, % ST-resolution at 60 mins was worse with alteplase 10mg vs placebo (23.1±53.9 vs 50.9±31.5) & in those with IMR≤32% ST-resolution at 60 mins was better with alteplase 20mg vs placebo (68.0±30.7 vs 39.1±43.2), p=0.002 for interaction. The CMR findings in the substudy & overall trial populations were consistent. Main results Placebo Alteplase 10mg Alteplase 20mg (n=53) (n=41) (n=50) IMR, median (IQR) 33.0 (17.0–57.0) 22.0 (17.0–42.0) 37.0 (20.0–57.8) p=0.15 p=0.78 CFR, median (IQR) 1.3 (1.1–1.8) 1.4 (1.1–1.9) 1.5 (1.1–2.0) p=0.92 p=0.74 RRR, median (IQR) 1.6 (1.3–2.2) 1.6 (1.4–2.6) 1.8 (1.3–2.4) p=0.69 p=0.81 P-values for comparison of alteplase with placebo. Conclusions In acute STEMI with ischaemic time ≤6 hrs, IMR, CFR or RRR post-PCI did not differ with alteplase vs placebo. In those with shorter ischaemic times ( Acknowledgement/Funding Dr Maznyczka is funded by a fellowship from the British Heart Foundation (FS/16/74/32573). T-TIME was funded by grant 12/170/4 from NIHR-EME

Background Ischemia and no obstructive epicardial coronary artery disease (INOCA) is a common clinical syndrome with distinct underlying causes. Objective To evaluate the prevalence and predictors of microvascular and/or vasospastic angina (MVA/VSA) in an unselected cohort of angina patients referred for invasive coronary angiography with suspected ischaemic heart disease in whom obstructive coronary artery disease (CAD) is excluded. Methods Prospective cohort study at two regional centres between November 2016 and December 2017 including patients with symptoms and/or signs of ischaemia prior to undergoing invasive coronary angiography (NCT03193294). Baseline risk was assessed (ASSIGN score) and validated questionnaires were completed prior to the angiogram including Rose angina, quality of life (EuroQOL [EQ-5D-5L]) and angina severity according to the Seattle Angina Questionnaire (SAQ). Patients with definite or probable angina without CAD [diameter stenosis 0.80] proceeded directly to assessment for disorders of coronary vasomotion. This involved an ad hoc interventional diagnostic procedure (IDP) using reference invasive tests for microvascular angina (MVA), vasospastic angina (VSA), both conditions or none. MVA and VSA groups were compared before logistic regression was performed to assess predictors of MVA and VSA. Results Three hundred and ninety-one patients with angina were recruited before undergoing invasive coronary angiography during the study period. Overall, 185 (47%) of subjects had INOCA and 151 of these underwent an IDP. INOCA patients reported similar angina burden with worse quality of life than CAD subjects (EQ5D-5L index 0.60 v 0.65 units; P=0.041). The mean age of patients who underwent the IDP was 60.9 years, 74% were female and their median predicted 10-year IHD risk was 18.6% (10.6, 31.4). 78 subjects (52%) had isolated microvascular angina, 25 (17%) had isolated vasospastic angina, 31 (20%) had both (MVA & VSA) only 17 (11%) had non-cardiac chest pain. Myocardial bridging of coronary artery was found in 22 (15%). Multivariate predictors of MVA included typical angina, inducible ischaemia but traditional cardiovascular risk factors were not associated. Smoking and age were independent predictors of VSA. Conclusion The majority of patients with symptoms and/or signs of ischemia and no obstructive disease have a diagnosis of microvascular and/or vasospastic angina. Traditional cardiovascular risk scores have limited discrimination for disorders of coronary vasomotion. Conflict of Interest Nil

Key Points Question: In patients undergoing primary percutaneous coronary intervention for acute ST-segment elevation myocardial infarction (STEMI), does adjunctive fibrinolytic therapy with low-dose intracoronary alteplase given after reperfusion and before stent implant reduce microvascular obstruction? Findings: In this randomized clinical trial that included 440 participants randomized to receive alteplase 20 mg, alteplase 10 mg, or placebo, the primary analysis demonstrated that the amount of microvascular obstruction (% left ventricular mass) revealed by magnetic resonance imaging was 3.5% in the alteplase 20-mg group and 2.3% in the placebo group, a difference that was not statistically significant. Meaning: Adjunctive low-dose intracoronary alteplase given early during primary percutaneous coronary intervention for acute ST-segment elevation myocardial infarction did not reduce microvascular obstruction. Abstract Importance: Microvascular obstruction commonly affects patients with acute ST-segment elevation myocardial infarction (STEMI) and is associated with adverse outcomes. Objective: To determine whether a therapeutic strategy involving low-dose intracoronary fibrinolytic therapy with alteplase infused early after coronary reperfusion will reduce microvascular obstruction. Design, Setting, and Participants: Between March 17, 2016, and December 21, 2017, 440 patients presenting at 11 hospitals in the United Kingdom within 6 hours of STEMI due to a proximal–mid-vessel occlusion of a major coronary artery were randomized in a 1:1:1 dose-ranging trial design. Patient follow-up to 3 months was completed on April 12, 2018. Interventions: Participants were randomly assigned to treatment with placebo (n = 151), alteplase 10 mg (n = 144), or alteplase 20 mg (n = 145) by manual infusion over 5 to 10 minutes. The intervention was scheduled to occur early during the primary PCI procedure, after reperfusion of the infarct-related coronary artery and before stent implant. Main Outcomes and Measures: The primary outcome was the amount of microvascular obstruction (% left ventricular mass) demonstrated by contrast-enhanced cardiac magnetic resonance imaging (MRI) conducted from days 2 through 7 after enrollment. The primary comparison was the alteplase 20-mg group vs the placebo group; if not significant, the alteplase 10-mg group vs the placebo group was considered a secondary analysis. Results: Recruitment stopped on December 21, 2017, because conditional power for the primary outcome based on a prespecified analysis of the first 267 randomized participants was less than 30% in both treatment groups (futility criterion). Among the 440 patients randomized (mean age, 60.5 years; 15% women), the primary end point was achieved in 396 patients (90%), 17 (3.9%) withdrew, and all others were followed up to 3 months. In the primary analysis, the mean microvascular obstruction did not differ between the 20-mg alteplase and placebo groups (3.5% vs 2.3%; estimated difference, 1.16%; 95% CI, −0.08% to 2.41%; P = .32) nor in the analysis of 10-mg alteplase vs placebo groups (2.6% vs 2.3%; estimated difference, 0.29%; 95% CI, −0.76% to 1.35%; P = .74). Major adverse cardiac events (cardiac death, nonfatal MI, unplanned hospitalization for heart failure) occurred in 15 patients (10.1%) in the placebo group, 18 (12.9%) in the 10-mg alteplase group, and 12 (8.2%) in the 20-mg alteplase group. Conclusions and Relevance: Among patients with acute STEMI presenting within 6 hours of symptoms, adjunctive low-dose intracoronary alteplase given during the primary percutaneous intervention did not reduce microvascular obstruction. The study findings do not support this treatment. Trial Registration: ClinicalTrials.gov Identifier: NCT02257294

Background Invasive measures of microvascular resistance in the culprit coronary artery have potential for risk stratification in acute ST‐segment–elevation myocardial infarction. We aimed to investigate the pathological and prognostic significance of coronary thermodilution waveforms using a diagnostic guidewire. Methods and Results Coronary thermodilution was measured at the end of percutaneous coronary intervention, (PCI) and contrast‐enhanced cardiac magnetic resonance imaging (MRI) was intended on day 2 and 6 months later to assess left ventricular (LV) function and pathology. All‐cause death or first heart failure hospitalization was a pre‐specified outcome (median follow‐up duration 1469 days). Thermodilution recordings underwent core laboratory assessment. A total of 278 patients with acute ST‐segment elevation myocardial infarction EMI (72% male, 59±11 years) had coronary thermodilution measurements classified as narrow unimodal (n=143 [51%]), wide unimodal (n=100 [36%]), or bimodal (n=35 [13%]). Microvascular obstruction and myocardial hemorrhage were associated with the thermodilution waveform pattern ( P =0.007 and 0.011, respectively), and both pathologies were more prevalent in patients with a bimodal morphology. On multivariate analysis with baseline characteristics, thermodilution waveform status was a multivariable associate of microvascular obstruction (odds ratio [95% confidence interval]=5.29 [1.73, 16.22];, P =0.004) and myocardial hemorrhage (3.45 [1.16, 10.26]; P =0.026), but the relationship was not significant when index of microvascular resistance (IMR) >40 or change in index of microvascular resistance (5 per unit) was included. However, a bimodal thermodilution waveform was independently associated with all‐cause death and hospitalization for heart failure (odds ratio [95% confidence interval]=2.70 [1.10, 6.63]; P =0.031), independent of index of microvascular resistance>40, ST‐segment resolution, and TIMI (Thrombolysis in Myocardial Infarction) Myocardial Perfusion Grade. Conclusions The thermodilution waveform in the culprit coronary artery is a biomarker of prognosis and may be useful for risk stratification immediately after reperfusion therapy.

The index of microvascular resistance (IMR) predicts presence of microvascular obstruction (MVO) on cardiovascular magnetic resonance (CMR) imaging & prognosis in acute STEMI, but discordance between IMR & MVO occurs in about one third of cases. We studied the predictive value of a new parameter

Background— Distal coronary to aortic pressure ratio (Pd/Pa) and instantaneous wave-free ratio (iFR) are indices of functional significance of a coronary stenosis measured without hyperemia. It has been suggested that iFR has superior diagnostic accuracy to Pd/Pa when compared with fractional flow reserve (FFR). We hypothesized that in comparison with FFR, revascularization decisions based on either binary cutoff values for iFR and Pd/Pa or hybrid strategies incorporating iFR or Pd/Pa will result in similar levels of disagreement. Methods and Results— This is a prospective study in consecutive patients undergoing FFR for clinical indications using proprietary software to calculate iFR. We measured Pd/Pa, iFR, FFR, and hyperemic iFR. Diagnostic accuracy versus FFR ≤0.80 was calculated using binary cutoff values of ≤0.90 for iFR and ≤0.92 for Pd/Pa, and adenosine zones for iFR of 0.86 to 0.93 and Pd/Pa of 0.87 to 0.94 in the hybrid strategy. One hundred ninety-seven patients with 257 stenoses (mean diameter stenosis 48%) were studied. Using binary cutoffs, diagnostic accuracy was similar for iFR and resting Pd/Pa with misclassification rates of 21% versus 20.2% ( P =0.85). In the hybrid analysis, 54% of iFR cases and 53% of Pd/Pa cases were outside the adenosine zone and rates of misclassification were 9.4% versus 11.9% ( P =0.55). Conclusions— Binary cutoff values for iFR and Pd/Pa result in misclassification of 1 in 5 lesions. Using a hybrid strategy, approximately half of the patients do not receive adenosine, but 1 in 10 lesions are still misclassified. The use of nonhyperemic indices of stenosis severity cannot be recommended for decision making in the catheterization laboratory. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT02377310.

Supplemental Digital Content is available in the text., The natural history and pathophysiological significance of tissue remodeling in the myocardial remote zone after acute ST-elevation myocardial infarction (STEMI) is incompletely understood. Extracellular volume (ECV) in myocardial regions of interest can now be measured with cardiac magnetic resonance imaging. Patients who sustained an acute STEMI were enrolled in a cohort study (BHF MR-MI [British Heart Foundation Magnetic Resonance Imaging in Acute ST-Segment Elevation Myocardial Infarction study]). Cardiac magnetic resonance was performed at 1.5 Tesla at 2 days and 6 months post STEMI. T1 modified Look-Locker inversion recovery mapping was performed before and 15 minutes after contrast (0.15 mmol/kg gadoterate meglumine) in 140 patients at 2 days post STEMI (mean age: 59 years, 76% male) and in 131 patients at 6 months post STEMI. Remote zone ECV was lower than infarct zone ECV (25.6±2.8% versus 51.4±8.9%; P

The index of microvascular resistance (IMR) is a direct, invasive test of coronary microvascular resistance [(1)][1]. When measured in the culprit coronary artery after emergency percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI), IMR is well established

Current clinical practice dictates that invasive management strategies frequently are adopted in patients with both ST-segment elevation and non–ST-segment elevation acute coronary syndromes. Such strategies rely on obtaining vascular access and, as such, are not always technically feasible. We report a case in which cardiac computed tomography was used to great effect in the diagnostic and (targeted) interventional management of a patient who was the recipient of a previous coronary artery bypass grafting and presented with global myocardial ischemia, in whom the lack of peripheral pulses had previously rendered an early invasive strategy hazardous.

Background— The US Food and Drug Administration recently concluded that data on off-label drug-eluting stent (DES) safety are limited. However, in actual clinical practice, DES are often used for off-label indications, and observational studies demonstrate that complications are higher when compared with on-label use. We aimed to determine whether clinical outcomes differ after DES and bare-metal stent implantation in a patient cohort defined by DES off-label indications. Methods and Results— We used the national revascularization registry in Scotland to identify patients who underwent coronary stenting for an off-label indication between January 2003 and September 2005. Individual-level linkage to comprehensive national admission and death databases was used to ascertain the end points of death, myocardial infarction, and target-vessel revascularization. We calculated propensity scores on the basis of clinical, demographic, and angiographic variables and matched DES to bare-metal stents on a 1:1 basis. The final study population consisted of 1642 patients, well matched for important covariables at baseline. Event-free survival was calculated over 24 months with the Kaplan-Meier method. All-cause death was more common after bare-metal stent implantation during follow-up (7.7% versus 6.6%; hazard ratio 0.63; 95% confidence interval, 0.40 to 0.99; P =0.04). No difference in the rates of myocardial infarction were noted (7.3% versus 7.5%; hazard ratio 1.02; 95% confidence interval, 0.69 to 1.54; P =0.92). Target-vessel revascularization was reduced in patients treated with DES (13.9% versus 10.7%; hazard ratio 0.67; 95% confidence interval, 0.49 to 0.93; P =0.02). Conclusions— At 24 months, patients treated with DES for off-label indications had lower rates of death and target-vessel revascularization and similar rates of myocardial infarction, as compared with patients treated with bare-metal stents.

To determine whether drug-eluting stent (DES) use varies among Scottish hospitals, and the extent to which any variations are explained by differences between operators, patients and lesions.Multi-level analysis of consecutive patients treated with percutaneous coronary intervention (PCI) between April 2005 and March 2006 in Scotland, using the Scottish Coronary Revascularization Registry.A total of 38 operators performed 5967 PCI procedures on 8489 lesions. Crude level of DES use was 47.6%, and the results varied among hospitals (range 30.6-61.8%, chi(2) = 341.6, P0.0001). There was significant between-operator variation in the null model. This was attenuated by the addition of hospital as a fixed effect. Nonetheless, the final model demonstrated significant between-operator variability [sigma(2) = 0.486 (0.249-0.971)] and between-hospital variation, after case-mix adjustment.Within Scotland, marked variation existed among hospitals in the use of DES. Operator was the most important factor at patient level, and hospital of treatment, rather than case-mix, was the most important modifier of between-operator variation. Patient selection for DES is complex and may contribute to much of the variations demonstrated. Consensus criteria would provide more detail than is included in current guidance, may aid decision-making for individual patients, reduce opportunity costs and ensure equity of access.

Background— The use of fractional flow reserve (FFR) in acute coronary syndromes is controversial. The British Heart Foundation Fractional Flow Reserve Versus Angiography in Guiding Management to Optimize Outcomes in Non-ST-Elevation Myocardial Infarction (FAMOUS-NSTEMI) study (NCT01764334) has recently demonstrated the safety and feasibility of FFR measurement in patients with non–ST-segment–elevation myocardial infarction. We report the findings of the cardiac magnetic resonance (CMR) substudy to assess the diagnostic accuracy of FFR compared with 3.0-T stress CMR perfusion. Methods and Results— One hundred six patients with non–ST-segment–elevation myocardial infarction who had been referred for early invasive management were included from 2 centers. FFR was measured in all major patent epicardial coronary arteries with a visual stenosis estimated at ≥30%, and if percutaneous coronary intervention was performed, an FFR assessment was repeated. Myocardial perfusion was assessed with stress perfusion CMR at 3 T. The mean age was 56.7±9.8 years; 82.6% were men. Mean time from FFR evaluation to CMR was 6.1±3.1 days. The mean±SD left ventricular ejection fraction was 58.2±9.1%. Mean infarct size was 5.4±7.1%, and mean troponin concentration was 5.2±9.2 μg/L. There were 34 fixed and 160 inducible perfusion defects. There was a negative correlation between the number of segments with a perfusion abnormality and FFR ( r =−0.77; P P Conclusions— FFR in patients with recent non–ST-segment–elevation myocardial infarction showed high concordance with myocardial perfusion in matched territories as revealed by 3.0-T stress perfusion CMR. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT02073422.

The significance of remote myocardium in the natural history of STEMI is uncertain. Cardiac magnetic resonance (CMR) depicts left ventricular (LV) dimension and pathology. Native T1 quantified by CMR (T1 proton relaxation time, milliseconds) is a fundamental tissue property determined by water

Background: Myocardial longitudinal relaxation time (T1, ms) is a fundamental magnetic property of tissue that is related to water content and mobility. The pathophysiological and prognostic importance of native myocardial T1 values in acute STEMI patients is unknown. We aimed to assess the clinical significance of infarct tissue characteristics using native T1 cardiac magnetic resonance (CMR).\ud \ud Methods: We performed a prospective single center cohort study in reperfused STEMI patients who underwent CMR 2 days and 6 months post-MI. Native T1 CMR (MOLLI investigational prototype sequence: 3 (3) 3 (3) 5) was measured in myocardial regions-of-interest. The area-at-risk and infarct territory were depicted with T1 mapping and late gadolinium contrast enhancement imaging, respectively. All-cause death or heart failure hospitalization was a pre-specified outcome that was assessed during follow-up.\ud \ud Results: 300 STEMI patients (mean±SD age 59±12 years, 74% male, 114 with anterior STEMI) gave informed consent and had CMR (14 July 2011 - 22 November 2012). Of these, 288 STEMI patients had evaluable T1 maps and follow-up assessments (median duration 845 days). Infarct size was 18 ±14% of left ventricular mass. Microvascular obstruction occurred in 160 (55.6%) patients. Native T1 within the area-at-risk (1097 ±52 ms) was higher than in the remote zone (961 ±25 ms; p

Background:\ud Myocardial longitudinal relaxation time (T1, ms) is a fundamental magnetic property of tissue that is related to water content and mobility. The pathophysiological and prognostic importance of native myocardial T1 values in acute ST-elevation myocardial infarction (STEMI) patients is unknown. We aimed to assess the clinical significance of infarct core native T1.\ud Methods:\ud We performed a prospective single center cohort study in reperfused STEMI patients who underwent CMR 2 days and 6 months post-MI. Native T1 CMR (MOLLI investigational prototype sequence: 3 (3) 3 (3) 5) was measured in myocardial regions-of-interest. The infarct territory and microvascular obstruction (MVO) were depicted with late gadolinium enhancement CMR. Adverse remodeling was defined as an increase in LV end-diastolic volume (LVEDV) ≥ 20% at 6 months. All-cause death or heart failure hospitalization was a pre-specified outcome that was assessed during follow-up.\ud \ud Results:\ud 300 STEMI patients (mean±SD age 59±12 years, 74% male, 114 with anterior STEMI) gave informed consent and had CMR (14 July 2011 - 22 November 2012). Of these, 288 STEMI patients had evaluable T1 maps. Infarct size was 18 ±14% of LV mass. One hundred and forty five (50%) of 288 patients had late MVO, whereas 160 (56%) patients had infarct core pathology revealed by native T1. Native T1 within the infarct core (996.9±57.3; p

AIM: To assess the effect of changing clinical practice on the costs and outcomes of percutaneous coronary intervention (PCI) between 1998 and 2002. SETTING: Two tertiary interventional centres.PATIENTS: Consecutive patients undergoing PCI over a 12-month period between 1998 and 2002.DESIGN: Comparative observational study of costs and 12-month clinical outcomes of consecutive PCI procedures in 1998 (n = 1047) and 2002 (n = 1346). Clinical data were recorded in the Scottish PCI register. Repeat PCI, coronary artery bypass graft and mortality were obtained by record linkage. Costs of equipment were calculated using a computerised bar-code system and standard National Health Service reference costs.RESULTS: Between 1998 and 2002, the use of bare metal stents increased from 44% to 81%, and the use of glycoprotein IIB/IIIA inhibitors increased from 0% to 14% of cases. During this time, a significant reduction was observed in repeat target-vessel PCI (from 8.4% to 5.1%, p = 0.001), any repeat PCI (from 11.7% to 9.2%, p = 0.05) and any repeat revascularisation (from 15.1% to 11.3%, p = 0.009) within 12 months. Significantly higher cost per case in 2002 compared with 1998 (mean (standard deviation) 2311 pounds (1158) v 1785 pounds (907), pCONCLUSIONS: Greater use of stents and glycoprotein IIb/IIIa inhibitors between 1998 and 2002 has been accompanied by a marked reduction in the need for repeat revascularisation. Longer duration of hospital stay for non-elective cases is mainly responsible for increasing costs. Strategies to reduce the length of stay could considerably reduce the costs of PCI.